The HBx protein of hepatitis B virus has been shown to induce hepatocellular carcinoma in transgenic mice as direct evidence for its involvement in hepatocarcinogenesis. In these transgenic mice, however, it is not clear why hepatocytes do not acquire a neoplastic phenotype by 13 months old despite the continuous growth stimulation by the HBx protein from 2 months old. In this study, we show that the accelerated proliferation of hepatocytes is counterbalanced by apoptosis, which maintains liver homeostasis. A decrease in the extent of apoptosis seems to precede the emergence of neoplasia in the transgenic mouse liver. The disappearance or block of apoptotic signals, which may be the result of additional genetic or epigenetic aberrations, may result in the preneoplastic hepatocytes becoming neoplastic.